The chemical nature of the main central excitatory transmitter: A critical appraisal based upon release studies and synaptic vesicle localization

doi:10.1016/0306-4522(93)90355-J

Neuroscience

Volume 56, Issue 3, October 1993, Pages 539-555

https://doi.org/10.1016/0306-4522(93)90355-J Get rights and content

Abstract

The chemical nature of the central transmitter responsible for fast excitatory events and other related phenomena is analysed against the historical background that has progressively clarified the structure and function of central synapses. One of the problems posed by research in this field has been whether one or more of the numerous excitatory substances endogenous to the brain is responsible for fast excitatory synaptic transmission, or if such a substance is, or was, a previously unknown one. The second question is related to the presence in the CNS of three main receptor types related to fast excitatory transmission, the so-called α-amino-3-hydroxy-5-methylisoxazole propionic acid, kainate andN-methyld-aspartate receptors. This implies the possibility that each receptor type might have its own endogenous agonist, as has sometimes been suggested.

To answer such questions, an analysis was done of how different endogenous substances, includingl-glutamate,l-aspartate,l-cysteate,l-homocysteate,l-cysteine sulfinate,l-homocysteine sulfinate,N-acetyl-l-aspartyl glutamate, quinolinate,l-sulfoserine, S-sulfo-l-cysteine, as well as possible unknown compounds, were able to fulfil the more important criteria for transmitter identification, namely identity of action, induced release, and presence in synaptic vesicles.

The conclusion of this analysis is that glutamate is clearly the main central excitatory transmitter, because it acts on all three of the excitatory receptors, it is released by exocytosis and, above all, it is present in synaptic vesicles in a very high concentration, comparable to the estimated number of acetylcholine molecules in a quantum, i.e. 6000 molecules. Regarding a possible transmitter role for aspartate, for which a large body of evidence has been presented, it seems, when this evidence is carefully scrutinized, that it is either inconclusive, or else negative. This suggests that aspartate is not a classical central excitatory transmitter.

From this analysis, it is suggested that the terms α-amino-3-hydroxy-5-methylisoxazole propionic acid, kainate andN-methyl-d-aspartate receptors, should be changed to that of glutamate receptors, and, more specifically, to GLU_A, GLU_K and GLU_N receptors, respectively. When subtypes are described, a Roman numeral may be added, as in GLU_NI, GLU_NII, and so on.

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The chemical nature of the main central excitatory transmitter: A critical appraisal based upon release studies and synaptic vesicle localization

Abstract

Physiol. Behav.

Brain Res.

Brain Res.

Neurosci. Lett.

Neuron

Neuron

Biochim. biophys. Acta

Brain Res.

Trends Neurosci.

Biochem. biophys. Res. Commun.

Biochem. biophys. Res. Commun.

Biochem. biophys. Res. Commun.

Neurosci. Lett.

Brain Res.

Neuroscience

Brain Res. Rev.

Eur. J. Pharmac.

Brain Res

Neurosci. Lett.

Brain Res.

Prog. Neurobiol.

Brain Res.

Trends pharmac. Sci.

Brain Res.

Neurosci. Lett.

Brain Res.

Brain Res.

The distribution of substance P and 5-hydroxytryptamine in the central nervous system of the dog

J. Physiol. (Lond.)

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J. Physiol. (Lond.)

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J. Physiol (Lond.)

Electrophysiological actions of kainic acid and folates in thein vitro olfactory cortex slice

Nature

Inhibition by diazepam and γ-aminobutyric acid of depolarization-induced release of [14C]cysteine sulfinate and [3H]glutamate in rat hippocampal slices

J. Neurochem.

The non-NMDA receptors: types, protein structure and molecular biology

Trends pharmac. Sci.

Aspartate and glutamate as possible neurotransmitters in the visual cortex

J. Neurosci.

Dipeptides of glutamate and aspartate may be endogenous neuroexcitants in the rat hippocampal slice

J. Neurosci.

The effect of cochlear nerve lesion on the release of glutamate, aspartate and GABA from the cochlear nucleusin vitro

Expl Brain Res.

Properties of quisqualate-sensitivel-[3H]glutamate binding sites in rat brain

J. Neurochem.

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J. Physiol. (Lond.)

The synthesis, turnover and release of surplus acetylcholine in a sympathetic ganglion

J. Physiol. (Lond.)

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J. Physiol. (Lond.)

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Pharmac. Rev.

The Biochemical Basis of Neuropharmacology

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J. Neurochem.

Actions ofl- andd-homocysteate in rat CNS: a correlation between low-affinity uptake and the time courses of excitation by microelectrophoretically appliedl-glutamate analogues

J. Neurochem

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J. Physiol. (Lond.)

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J. Physiol. (Lond.)

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J. Physiol. (Lond.)

The chemical excitation of spinal neurones by certain acidic amino acids

J. Physiol. (Lond.)

Actions of amino acids on the isolated hemisected spinal cord of the toad

Br. J. Pharmac.

Inhibition by diazepam and γ-aminobutyric acid of depolarization-induced release of [¹⁴C]cysteine sulfinate and [³H]glutamate in rat hippocampal slices

Properties of quisqualate-sensitivel-[³H]glutamate binding sites in rat brain